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<p>β-arrestins, pivotal regulators of G protein-coupled receptor (GPCR) signaling, assemble with hundreds of GPCRs. How this assembly rises to functionally distinct complexes in which β-arrestin engages the GPCR tail, core or both, remains a central question. Here employing single-molecule force spectroscopy and molecular dynamics simulations, we monitor assembly of β<sub>2</sub>-adrenergic receptor (β<sub>2</sub>AR)–β-arrestin2 (βarr2) tail, core and tail–core complexes in phospholipid membranes and dissect their mechanical and kinetic stabilities. We show that βarr2 engages the phosphorylated β<sub>2</sub>AR carboxy-terminus (C-tail) within milliseconds, much faster than the active receptor core. In addition, the phospholipid membrane contributes substantially to complex stability, with phosphatidylinositol 4,5-bisphosphate (PIP<sub>2</sub>) modulating stability and conformation. While PIP<sub>2</sub> stabilizes the β<sub>2</sub>AR–βarr2 core, it precludes βarr2 from concomitantly binding the phosphorylated β<sub>2</sub>AR C-tail. βarr2 activation and PIP<sub>2</sub> strengthen βarr2–membrane association through insertion of the C-edge and finger loop. These findings establish PIP<sub>2</sub>, alongside ligand binding and receptor phosphorylation, as a central determinant of β<sub>2</sub>AR–βarr2 complex assembly, offering mechanistic insight into the regulation of GPCR signaling.</p>

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Factors modulating the assembly of human β2-adrenergic receptor–β-arrestin complexes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月31日

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  • Florian M. Wilhelm,
  • Kristyna Pluhackova,
  • John Janetzko,
  • Matthieu Masureel,
  • Erin Marsh,
  • Jesse Hudspeth,
  • Wenzel Gaßner,
  • Gebhard F. X. Schertler,
  • Brian K. Kobilka,
  • Daniel J. Müller

摘要

β-arrestins, pivotal regulators of G protein-coupled receptor (GPCR) signaling, assemble with hundreds of GPCRs. How this assembly rises to functionally distinct complexes in which β-arrestin engages the GPCR tail, core or both, remains a central question. Here employing single-molecule force spectroscopy and molecular dynamics simulations, we monitor assembly of β2-adrenergic receptor (β2AR)–β-arrestin2 (βarr2) tail, core and tail–core complexes in phospholipid membranes and dissect their mechanical and kinetic stabilities. We show that βarr2 engages the phosphorylated β2AR carboxy-terminus (C-tail) within milliseconds, much faster than the active receptor core. In addition, the phospholipid membrane contributes substantially to complex stability, with phosphatidylinositol 4,5-bisphosphate (PIP2) modulating stability and conformation. While PIP2 stabilizes the β2AR–βarr2 core, it precludes βarr2 from concomitantly binding the phosphorylated β2AR C-tail. βarr2 activation and PIP2 strengthen βarr2–membrane association through insertion of the C-edge and finger loop. These findings establish PIP2, alongside ligand binding and receptor phosphorylation, as a central determinant of β2AR–βarr2 complex assembly, offering mechanistic insight into the regulation of GPCR signaling.